Arteriosclerosis is a class of diseases characterized by the thickening and hardening of the arterial walls of blood vessels. Although all blood vessels are susceptible to this serious degenerative condition, the aorta and the coronary arteries serving the heart are most often affected. Arteriosclerosis is of profound clinical importance since it can increase the risk of heart attacks, myocardial infarctions, strokes, and aneurysms.
The traditional treatment for arteriosclerotic vessels has been coronary bypass surgery. More recently, however, vascular recanalization procedures for treating arteriosclerotic vessels have been developed. These procedures involve using intravascular devices threaded through blood vessels to the obstructed site, including for example, percutaneous transluminal angioplasty (PTA), also known as balloon angioplasty. Balloon angioplasty uses a catheter with a balloon tightly packed onto its tip. When the catheter reaches the obstruction, the balloon is inflated, and the atherosclerotic plaques are compressed against the vessel wall. A shortcoming of this and other intravascular procedures, however, is that in a number of individuals some of the treated vessels restenose (ie. the vessels narrow) by six months post-angioplastic treatment. The restenosis is thought to be due in part to mechanical injury to the walls of the blood vessels caused by the intravascular device.
The walls of most blood vessels are composed of three distinct layers, or tunics, surrounding a central tubular opening, the vessel lumen. The innermost layer that lines the vessel lumen is called the tunica intima. The middle layer, the tunica media, consists mostly of circularly arranged smooth muscle cells and connective tissue fibers. In a non-injured vessel the smooth muscle cells are normally not actively dividing. The outmost layer of the blood vessel wall, the tunica adventitia, is composed largely of collagen fibers that protect the blood vessel. Mechanical injury, resulting in damage to the tunica intima, initiates a number of events, including the release of chemicals such as platelet-derived growth factors (PDGF), which prompts the migration and proliferation of smooth muscle cells at the site of injury over many weeks.
Several methods for inhibiting smooth muscle cell proliferation following the use of an intravascular device have been reported. These include the administration of agents, including, for example, anti-proliferative agents such as cell cycle inhibitors and anti-coagulant agents, by local or systemic delivery systems. Delivery of agents systemically, however, has required dosages that are both prohibitively toxic and prohibitively costly. Local delivery of agents, for example heparin, as described in U.S. Pat. No. 4,824,436, has proven ineffective in inhibiting restenosis due in part to problems related to inadequate residence time at the site of injury before the agent diffuses to ineffective concentrations. Cell cycle inhibitors such as taxol, which do not react covalently and require prolonged residence time for effectiveness, are likely to have similar problems. In addition, prolonged residence times are likely to have a greater risk of toxicity.
Other methods reported for inhibiting smooth muscle cell proliferation involve locally delivering agents that are contained in sustained release formulations. In one example, agents contained within a physiologically compatible, biodegradable polymeric microparticle are delivered locally to the site of injury such that the agents are released from the arterial wall for 72 hours or more. U.S. Pat. No. 5,171,217. Still other methods reported for inhibiting smooth muscle cell proliferation involve administering photochemically activated agents by local delivery systems. In one example, photochemically activated agents, for example, 8-methoxypsoralen, are locally delivered to the site of injury and then activated by a visible light source. U.S. Pat. No. 5,354,774. Another approach is the use of radiation-emitting catheters or guide wires, which can cause damage to nucleic acid and inhibit smooth muscle cell proliferation. Each of these methods, however, requires an added level of complexity, namely incorporation of the agent on or within a sustained release formulation, photoactivation using a complex intravascular light source, or delivery of a radiation dose which requires the presence of a radiologist and presents exposure hazards to the attending personnel.
A need therefore exists for safer and less complex methods for inhibiting smooth muscle cell proliferation at a site of injury following vascular recanalization procedures.